Genetic effect of CCR3 and IL5RA gene polymorphisms on eosinophilia in asthmatic patients

Abstract

Background: Eosinophilic infiltration and peripheral blood eosinophilia in asthma require the cooperation of eosinophil-specific cytokines and chemokines and their receptors. Objective: We investigated the association of polymorphisms in CCR3 and IL5RA with asthma susceptibility or peripheral blood eosinophilia and the effects of the polymorphisms on receptor expression. Methods: Polymorphisms in CCR3 and IL5RA were identified and genotyped in 576 asthmatic patients and 180 healthy control subjects. CCR3 and IL-5 receptor a (IL-5R alpha) protein expression on eosinophils was measured by means of flow cytometry. Results: Although polymorphisms in CCR3 were not associated with asthma susceptibility, the CCR3 haplotype ht2 showed a negative gene dose effect on the eosinophil count (P =.003-.009). IL5RA c. -5091G>A was weakly associated with eosinophil count. The effects of ht2 were greater when paired with IL5RA c. -5091A (P =.001-002). CCR3 protein expression was higher on eosinophils of asthmatic patients without ht2 than in those with W. Asthmatic patients with the IL5RA c. -5091A allele showed higher IL-5R alpha expression than those who were homozygous for the G allele. Conclusion: The genetic association between CCR3 polymorphisms and the number of circulating eosinophils was revealed as a novel finding. These associations were more pronounced when the CCR3 polymorphisms were paired with polymorphisms in IL5RA. The protein expression levels of CCR3 and IL-5R alpha on peripheral blood eosinophils are associated with the polymorphisms on their own genes. Clinical implications: The identification of single nucleotide polymorphisms and haplotypes of CCR3 and IL5RA might be useful in developing markers for intermediate phenotypes of eosinophil number and in designing strategies to control diseases related to hypereosinophilia.